The acute clinical manifestations of Sickle-Cell Disease (SCD) can be effectively treated only by transfusion therapy, which also may provide some prophylactic protection. In this proposal, we aim to elucidate the target pathophysiology and mechanism of action of transfusion therapy, through detailed in vivo studies of the microcirculation in humans. In particular, we propose to study the cerebral microcirculation. We hypothesize that the cerebral pathophysiology of SCD can be rigorously explained by the combination of chronic anemia, leading to permanent vasodilatation and exhaustion of vascular reserve capacity, and occasional aggravation of rheological/embolic factors such as sickling, adhesion or aggregation. We will use Single-Photon Emission Computerized Tomography (SPECT) and 133Xe-rCBF techniques to image and quantify regional Cerebral Blood Flow (rCBF), Blood Volume (rCBV), local capillary hematocrit, and hypercapnic reactivity of cerebral resistance vessels. These procedures will be conducted in a total of 60 patients and 40 anemic controls, over a range of total hemoglobin and HbS fractions. Patients will be studied during pain crisis and different transfusion regimens, as well as at stable baseline. The immediate goal of the project is to develop cerebrovascular monitoring algorithms which can track, and potentially predict, pathophysiology. Ultimately, by establishing the relationship in brain among HbS, total Hb and O2 delivery in SCD, we aim to define an optimal transfusion regimen, and then evaluate its risk/benefit ratio in preventing cerebrovascular disease among susceptible patients, compared to alternative treatments.